Abstract
NLRX1, a mitochondrial NOD-like receptor (NLR) family protein, is a non-inflammasome-forming protein with diverse roles in cancer. While NLRX1 has been recognized as a tumor suppressor in colorectal and hepatocellular carcinomas, it appears to act as a tumor promoter in breast and head and neck cancers. This study explored the role of NLRX1 in prostate cancer (PCa), examining its impact on cell proliferation, apoptosis, migration, invasion, and tumor progression, as well as associated molecular mechanisms. Using TCGA data, the association between NLRX1 expression and PCa prognosis was evaluated. NLRX1 expression was upregulated under serum-free stress conditions. Silencing NLRX1 reduced cell proliferation in PC3 cells, but not in LNCaP cells. Additionally, NLRX1 knockdown inhibited migration and invasion, while promoting apoptosis under serum-free conditions. Mechanistically, NLRX1 knockdown reduced AKT and ERK phosphorylation in response to serum deprivation, EGF, and TGF-β, without affecting PDK1 activity under serum deprivation. Pharmacological data showed AKT and ERK as key regulators of viability and invasion, with AKT critical for growth and migration. Co-immunoprecipitation, confocal microscopic examination, domain binding, structural modeling, and molecular dynamics revealed a stable interaction between NLRX1's LRR domain and AKT's PH domain. NLRX1 facilitated cell proliferation, migration, invasion, and resistance to serum-free stress through direct interaction with AKT, highlighting NLRX1 as a promising biomarker for PCa progression.